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The microbiota-gut-brain axis is a key pathway perturbed by prolonged stressors to produce brain and behavioral disorders. Frontline healthcare workers (FHWs) fighting against COVID-19 typically experience stressful event sequences and manifest some mental symptoms; however, the role of gut microbiota in such stress-induced mental problems remains unclear. We investigated the association between the psychological stress of FHW and gut microbiota.We used full-length 16S rRNA gene sequencing to characterize the longitudinal changes in gut microbiota and investigated the impact of microbial changes on FHWs' mental status.Stressful events induced significant depression, anxiety, and stress in FHWs and disrupted the gut microbiome; gut dysbiosis persisted for at least half a year. Different microbes followed discrete trajectories during the half-year of follow-up. Microbes associated with mental health were mainly Faecalibacterium spp. and [Eubacterium] eligens group spp. with anti-inflammatory effects. Of note, the prediction model indicated that low abundance of [Eubacterium] hallii group uncultured bacterium and high abundance of Bacteroides eggerthii at Day 0 (immediately after the two-month frontline work) were significant determinants of the reappearance of post-traumatic stress symptoms in FHWs.The lack of metabolomic evidence and animal experiments result in the unclear mechanism of gut dysbiosis-related stress symptoms.The stressful event sequences of fighting against COVID-19 induce characteristic longitudinal changes in gut microbiota, which underlies dynamic mental state changes.

Evidence suggests that complex interactions between the immune system and brain have important etiological and therapeutic implications in schizophrenia. However, the detailed cellular and molecular basis of immune dysfunction in schizophrenia remains poorly characterized. To better understand the immune changes and molecular pathways, we systemically compared the cytokine responses of peripheral blood mononuclear cells (PBMCs) derived from patients with schizophrenia and controls against bacterial, fungal, and purified microbial ligands, and identified aberrant cytokine response patterns to various pathogens, as well as reduced cytokine production after stimulation with muramyl dipeptide (MDP) in schizophrenia. Subsequently, we performed single-cell RNA sequencing on unstimulated and stimulated PBMCs from patients and controls and revealed widespread suppression of antiviral and inflammatory programs as well as impaired chemokine/cytokine-receptor interaction networks in various immune cell subpopulations of schizophrenic patients after MDP stimulation. Moreover, serum MDP levels were elevated in these patients and correlated with the course of the disease, suggesting increased bacterial translocation along with disease progression. In vitro assays revealed that MDP pretreatment altered the functional response of normal PBMCs to its re-stimulation, which partially recapitulated the impaired immune function in schizophrenia. In conclusion, we delineated the molecular and cellular landscape of impaired immune function in schizophrenia, and proposed a mutual interplay between innate immune impairment, reduced pathogen clearance, increased MDP translocation along schizophrenia development, and blunted innate immune response. These findings provide new insights into the pathogenic mechanisms that drive systemic immune activation, neuroinflammation, and brain abnormalities in schizophrenia.

Background Different countries have differences in social and cultural context and health system, which may affect the clinical characteristics of psychiatric inpatients. This study was the first to compare cross-cultural differences in the clinical characteristics of psychiatric inpatients in three hospitals from Western China and America. Methods Overall, 905 and 1318 patients from three hospitals, one in America and two in Western China, respectively, were included. We used a standardised protocol and data collection procedure to record inpatients’ sociodemographic and clinical characteristics. Results Significant differences were found between hospitals from the two countries. Positive symptoms were the main reason for admission in the Chinese hospitals, while reported suicide and self-injury symptoms more frequently led to hospital admission in America. Moreover, there were more inpatients with combined substance abuse in the American hospital (97.6% vs. 1.9%, P < 0.001). The length of stay (LOS) in America was generally shorter than in China (10.5 ± 11.9 vs. 20.7 ± 13.4, P < 0.001). The dosage of antipsychotic drugs used in the American hospital was higher than in China (275.1 ± 306.9 mg vs. 238.3 ± 212.5 mg, P = 0.002). Regression analysis showed that male sex, older age, retirees, being admitted because of physical symptoms, and using higher doses of antipsychotic drugs were significantly associated with longer hospitalisation in the American hospital (P < 0.05). Comparatively, patients who were divorced, experiencing suicidal ideation, admitted involuntarily, admitted because of physical, depression, or anxiety symptoms, and using higher doses of antipsychotic drugs had longer hospitalisation in Chinese hospitals (P < 0.05). Conclusion Significant variations in clinical characteristics of inpatients were found between hospitals from Western China and America. The LOS in Chinese hospitals was significantly longer, but patients used higher doses of antipsychotic drugs in the American hospital. Admission due to physical symptoms and the use of higher dosage drugs were related to longer LOS in both countries.

Aim Post-stroke depression (PSD) is one of the most frequent neuropsychiatric disorders associated with stroke characterized by depression. The neuroplasticity hypothesis postulates that loss of brain-derived neurotrophic factor (BDNF) plays a major role in pathophysiology of PSD, and restoration of it may represent a critical mechanism underlying antidepressant efficacy. Methods In previous studies, we designed a new fusion gene, HA2TAT-BDNF, and cloned it into adenovirus associated virus (AAV) to construct the BDNF-HA2TAT/AAV for the delivery of BDNF to central nervous system (CNS) via nose-brain pathway. In this study, we used it to explore the antidepressant effects on PSD rats through behavioral and various histological methods, and try to find out its specific mechanism. Results Compared with the control group, the PSD+AAV group showed decreased sucrose consumption percentage in the sucrose preference test (SPT) (P 0.05, P >0.05), showing an adequate antidepressant effect. Compared with the control group, the concentrations of BDNF mRNA and protein in the hippocampus (P 0.05, P < 0.05), without notable change in the hippocampus (P < 0.05, P < 0.001) of PSD+BDNF rats. Conclusion These results suggest that BDNF reductions in the prefrontal cortex and hippocampus are associated with the development of post-stroke depression, and that increased levels of BDNF in the prefrontal cortex could be used as a therapeutic target to treat PSD. However, the exact mechanism of BDNF action remains unclear in this regard, hindering the wider application of our method. We expect that our research could facilitate the exploration of pathogenesis and the new treatment method of PSD.

BackgroundThis study aimed to examine the efficacy of combining paroxetine and mirtazapine v. switching to mirtazapine, for patients with major depressive disorder (MDD) who have had an insufficient response to SSRI monotherapy (paroxetine) after the first 2 weeks of treatment.MethodsThis double-blind, randomized, placebo-controlled, three-arm study recruited participants from five hospitals in China. Eligible participants were aged 18–60 years with MDD of at least moderate severity. Participants received paroxetine during a 2-week open-label phase and patients who had not achieved early improvement were randomized to paroxetine, mirtazapine or paroxetine combined with mirtazapine for 6 weeks. The primary outcome was improvement on the Hamilton Rating Scale for Depression 17-item (HAMD-17) scores 6 weeks after randomization.ResultsA total of 204 patients who showed early non-response to paroxetine monotherapy were randomly assigned to receive either mirtazapine and placebo (n = 68), paroxetine and placebo (n = 68) or mirtazapine and paroxetine (n = 68), with 164 patients completing the outcome assessment. At week 8, the least squares (LS) mean change of HAMD-17 scores did not significantly differ among the three groups, (12.98 points) in the mirtazapine group, (12.50 points) in the paroxetine group and (13.27 points) in the mirtazapine plus paroxetine combination group. Participants in the paroxetine monotherapy group were least likely to experience adverse effects.ConclusionsAfter 8 weeks follow-up, paroxetine monotherapy, mirtazapine monotherapy and paroxetine/mirtazapine combination therapy were equally effective in non-improvers at 2 weeks. The results of this trial do not support a recommendation to routinely offer additional treatment or a switch in treatment strategies for MDD patients who do not show early improvement after 2 weeks of antidepressant treatment.

Accumulating evidence suggests that gut microbiota plays a role in the pathogenesis of schizophrenia via the microbiota-gut-brain axis. This study sought to investigate whether transplantation of fecal microbiota from drug-free patients with schizophrenia into specific pathogen-free mice could cause schizophrenia-like behavioral abnormalities. The results revealed that transplantation of fecal microbiota from schizophrenic patients into antibiotic-treated mice caused behavioral abnormalities such as psychomotor hyperactivity, impaired learning and memory in the recipient animals. These mice also showed elevation of the kynurenine-kynurenic acid pathway of tryptophan degradation in both periphery and brain, as well as increased basal extracellular dopamine in prefrontal cortex and 5-hydroxytryptamine in hippocampus, compared with their counterparts receiving feces from healthy controls. Furthermore, colonic luminal filtrates from the mice transplanted with patients' fecal microbiota increased both kynurenic acid synthesis and kynurenine aminotransferase II activity in cultured hepatocytes and forebrain cortical slices. Sixty species of donor-derived bacteria showed significant difference between the mice colonized with the patients' and the controls' fecal microbiota, highlighting 78 differentially enriched functional modules including tryptophan biosynthesis function. In conclusion, our study suggests that the abnormalities in the composition of gut microbiota contribute to the pathogenesis of schizophrenia partially through the manipulation of tryptophan-kynurenine metabolism.

ObjectiveGut microbiota dysbiosis and aberrant gut-brain functional modules including short-chain fatty acid (SCFA) production and long-lasting immune activation (IA) are presented in schizophrenia. Given the key roles of gut microbiota and SCFA in shaping immunity, we propose that dysbiosis-induced SCFA upregulation could contribute to IA and behavioral symptoms in schizophrenia.DesignGut microbiota, SCFA, and IA biomarkers were compared between schizophrenic patients and healthy controls. The roles of SCFA in schizophrenia-related IA were analyzed in cultured peripheral blood mononuclear cells (PBMCs) and a mouse model of schizophrenia. The effects of SCFAs on schizophrenia-related phenotypes were analyzed in both human and mouse.ResultsBoth microbial-derived SCFA and SCFA-producing bacteria were elevated in the guts of schizophrenic patients, and this increased SCFA production in gut was associated with IA in schizophrenia. The microbiome signature underpinning schizophrenia-related IA includes increased diversity and increased SCFA-producing bacteria and inflammation-associated bacteria. The impact of SCFAs on immune responses of cultured PBMC depend on the diagnosis and IA status of donors. Small-molecule serum filtrates from immune-activated schizophrenic patients increased the inflammatory response of PBMCs from healthy volunteers, which can be enhanced and attenuated by SCFAs supplementation and inhibition of SCFA signaling, respectively. Chronically elevated SCFAs in adolescence induced neuroinflammation and schizophrenia-like behaviors in adult mice. Moreover, chronically elevated SCFAs in adult mice prenatally exposed to IA potentiated their expression of schizophrenia-like behaviors.Conclusionmicrobiota-derived SCFAs are important mediators of dysregulated gut-brain axis and participant in pathogenesis via enhance IA in schizophrenia.SummarySignificance of this studyWhat is already known about this subject?➢ Schizophrenia pathogenesis goes beyond the brain since increasing peripheral abnormalities are revealed including gut microbiota dysbiosis, GI dysfunction, and systemic immune activation (IA).➢Systemic IA/inflammation contributes to the neuroinflammation and brain impairment underlying schizophrenia, and adjunctive immunotherapy can improve psychotic symptoms.➢Short-chain fatty acids (SCFA) mediate the microbiota-gut-brain communication and modulate several pathways involved in schizophrenia, including pathways of immunity and neurotransmitters.What are the new findings?➢Patients with schizophrenia displayed increased rates of IA and increased SCFA production compared with healthy controls, and increased SCFA is associated with IA in patients.➢A unique microbiota signature including enriched SCFA-producing bacterial species can distinguish patients with IA from other patients and controls.➢Small molecules in the serum of immune-activated patients with schizophrenia enhance LPS-induced immune response of cultured peripheral blood mononuclear cell (PBMCs), which is partially mediated by SCFA signaling.➢SCFA intake upregulates both peripheral and brain inflammation and potentiates the expression of schizophrenia-like behaviors in mice prenatally exposed to IA.How might it impact on clinical practice in the foreseeable future?➢Interference of SCFA signaling or targeted destruction of SCFA-producing bacteria may provide a new approach for the prevention and treatment of schizophrenia.➢Immune activation status of patients should be an important condition considered when selecting immunotherapy for future precision psychiatric therapy.

ObjectiveTo compare 22 oral drugs, cognitive behavior therapy (CBT), and their combination treatments for the acute treatment of adults with panic disorder in terms of remission rate and acceptability.DesignSystematic review and network meta-analysisData sourcesPubMed, Web of Science, Cochrane Central Register of Controlled Trials, and Embase databases from their inception up to May 26, 2019.Study selectionRandomized controlled clinical trials (RCTs) of any oral drugs, CBT, CBT combined with any drug, or placebo in the acute treatment of adults with panic disorder diagnosed according to standard operationalized criteria. The primary outcomes were efficacy (remission rate) and acceptability (treatment discontinuations due to any cause).ResultsWe identified 6585 reports that included 68 full-text RCTs involving 11101 patients. In terms of efficacy, 13 (68%) of 19 interventions were associated with higher remission rates than those of for placebo, with ORs ranging from 2.1 (95% credible interval [CrI] = 1.1 to 4.0) for sertraline to 13 (CrI = 4.5 to 44) for CBT combined with any drug. Regarding acceptability, alprazolam, imipramine, and etizolam were associated with lower dropout rates, with ORs ranging from 0.23 (CrI = 0.15 to 0.33) for alprazolam to 0.076 (CrI = 0.0021 to 0.77) for etizolam. Most of the differences between the other interventions were unclear. In head-to-head analyses, CBT combined with any drug was more effective than the other interventions, but it was no associated with an improvement in acceptability (OR = 0.12 to 0.219).ConclusionsCBT combined with any drug was more effective than the other interventions analyzed in this study. CBT alone did not differ significantly from other drugs alone. We found that most drugs are effective against panic disorder, but they exhibit different acceptability and tolerability profiles.What is already known on this topicSome randomized controlled trials indicated that combined therapy are more effective than drug alone or cognitive behavior therapy alone. Nevertheless, drug monotherapy, cognitive behavior therapy, and combination therapy had never been compared in a comprehensive network meta-analysis. With this evidence gap remaining, the availability of reliable evidence of the relative merits of multiple interventions is essential to ensuring that clinicians choose the best option for each individual patient.What this study addsThis network meta-analysis is the first to evaluate the relative merits of cognitive behavior therapy, cognitive behavior therapy combined with any drug, and 22 oral drugs in the field of panic disorder. The results showed a significant higher remission rates for cognitive behavior therapy combined with any drug than those of the other interventions. Cognitive behavior therapy alone was superior to placebo but did not differ significantly from other active drugs. Additionally, paroxetine, venlafaxine, fluoxetine, sertraline, and clonazepam are more recommendable than the other drugs based on their remission rates, scores on panic-symptoms scales, and acceptability.

Evidence is mounting that the gut-brain axis plays an important role in mental diseases fueling mechanistic investigations to provide a basis for future targeted interventions. However, shotgun metagenomic data from treatment-naïve patients are scarce hampering comprehensive analyses of the complex interaction between the gut microbiota and the brain. Here we explore the fecal microbiome based on 90 medication-free schizophrenia patients and 81 controls and identify a microbial species classifier distinguishing patients from controls with an area under the receiver operating characteristic curve (AUC) of 0.896, and replicate the microbiome-based disease classifier in 45 patients and 45 controls (AUC = 0.765). Functional potentials associated with schizophrenia include differences in short-chain fatty acids synthesis, tryptophan metabolism, and synthesis/degradation of neurotransmitters. Transplantation of a schizophrenia-enriched bacterium, Streptococcus vestibularis, appear to induces deficits in social behaviors, and alters neurotransmitter levels in peripheral tissues in recipient mice. Our findings provide new leads for further investigations in cohort studies and animal models., Gut microbiome has been linked to neurogenerative diseases. Here, the authors present a metagenome-wide association study of schizophrenia (SZ) in human cohorts and identify SZ-associated specific gut-brain functional modules and pathways including SCFAs and neurotransmitters.

Previous findings on the dysfunction of hypothalamic-pituitary-adrenal (HPA) axis in generalized anxiety disorder (GAD) are controversial, and the molecular mechanisms underlying such dysfunction remain unclear. We analyzed the methylation status of the NR3C1 1F promoter and the expression of glucocorticoid receptor-α isoform (GRα) in peripheral blood mononuclear cells (PMBCs), the basal cortisol level in serum, and a functional neuroendocrine marker for GR sensitivity in the PMBCs in 64 patients with current GAD and 85 healthy controls. We found that patients with GAD had significantly elevated levels of morning basal serum cortisol (P

Both genetic factors and early life adversity play major roles in the etiology of schizophrenia. Our previous studies indicated that social isolation (SI) during early postnatal development leads to several lasting abnormal behavioral and pathophysiological features resembling the core symptoms of some human neuropsychiatric disorders in mice. The glutamate and dopamine hypotheses are tightly linked to the development of schizophrenia. The cross-talk between glutamate N-methyl-D-aspartate acid receptors and dopamine receptors is associated with histidine triad nucleotide binding protein 1 (HINT1), which is correlated with diverse psychiatric disorders. We examined the effects of SI on schizophrenia-like behavior and used enzyme-linked immunosorbent assays to investigate the expression levels of HINT1, the NR1 subunit of N-methyl-D-aspartate acid receptor, and dopamine type 2 receptor (D2R) in C57 mice. We found that SI leads to a series of schizophrenia-related deficits, such as social withdrawal, anxiety disorder, cognitive impairments, and sensorimotor gating disturbances. These abnormal phenotypes paralleled changes of HINT1, NR1, and D2R. SI may be considered a robust model of the effects of early life stress on the schizophrenia-related behaviors in mice. Potential interactions among HINT1, NR1, and D2R may underlie the behavioral deficits induced by SI.

// Fei Liu 1, 2, * , You-ping Liu 1, 3, * , Gang Lei 1 , Peng Liu 1 , Zheng Chu 1 , Cheng-ge Gao 4 , Yong-hui Dang 1, 5, 6 1 College of Medicine & Forensics, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, Shaanxi, PR China 2 Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, PR China 3 Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China 4 Department of Psychiatry, First Affiliated Hospital of Xi’an Jiaotong University Health Science Center, Xi’an, 710061, Shaanxi, PR China 5 Key Laboratory of the Health Ministry for Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi’an 710061, Shaanxi, PR China 6 Key Laboratory of Forensic Medicine of Shaanxi Province, Xi’an Jiaotong University Health Science Center, Xi’an 710061, Shaanxi, PR China * These authors have contributed equally to this work Correspondence to: Yong-hui Dang, email: psydyh@mail.xjtu.edu.cn Keywords: social isolation, depression, NT4-NAP/AAV, intranasal administration, antidepressant Received: October 09, 2016 Accepted: December 13, 2016 Published: December 29, 2016 ABSTRACT The purpose of the present study was to observe the depression-like behavior induced by social isolation; detect the antidepressant effect of a recombinant adeno-associated virus (AAV) expressing NAP on social isolation mice by intranasal delivery. After construction of NT4-NAP/AAV, expression of NAP was confirmed in vitro . 3-week-old C57/BL mice were bred individually in cages as social isolation-rearing. Six weeks later, the first subset of mice underwent behavioral tests and western blot; the second was for enzyme-linked immunosorbent assay. NT4-NAP/AAV was delivered quaque die by nasal administration for consecutive 10 days before behavioral test. Several depression-like behaviors were observed in social isolation mice, including decreased relative sucrose preference, longer immobility time in forced swimming test, lower plasma corticosterone and decreased brain-derived neurotrophic factor in hippocampus. Thus, social isolation procedure appears to be an animal model of depression with good face and construct validity. What’s more, the antidepressant effect in social isolation-rearing mice was observed after intranasal administration of NT4-NAP/AAV, suggesting that this might be a promising therapeutic strategy for depressive disorder.

Emerging evidence has linked the gut microbiota to schizophrenia. However, the functional changes in the gut microbiota and the biological role of individual bacterial species in schizophrenia have not been explored systematically. Here, we characterized the gut microbiota in schizophrenia using shotgun metagenomic sequencing of feces from a discovery cohort of 90 drug-free patients and 81 controls, as well as a validation cohort of 45 patients taking antipsychotics and 45 controls. We screened 83 schizophrenia-associated bacterial species and constructed a classifier comprising 26 microbial biomarkers that distinguished patients from controls with a 0.896 area under the receiver operating characteristics curve (AUC) in the discovery cohort and 0.765 AUC in the validation cohort. Our analysis of fecal metagenomes revealed that schizophrenia-associated gut–brain modules included short-chain fatty acids synthesis, tryptophan metabolism, and synthesis/degradation of neurotransmitters including glutamate, γ-aminobutyric acid, and nitric oxide. The schizophrenia-enriched gut bacterial species include several oral cavity-resident microbes, such as Streptococcus vestibularis. We transplanted Streptococcus vestibularis into the gut of the mice with antibiotic-induced microbiota depletion to explore its functional role. We observed that this microbe transiently inhabited the mouse gut and this was followed by hyperactivity and deficit in social behaviors, accompanied with altered neurotransmitter levels in peripheral tissues. In conclusion, our study identified 26 schizophrenia-associated bacterial species representing potential microbial targets for future treatment, as well as gut–brain modules, some of which may give rise to new microbial metabolites involved in the development of schizophrenia.

Age differences exist in many aspects in patients with major depressive disorder (MDD). The present study aims to examine the effect of age on treatment outcomes in first-episode MDD.A total of 982 first-episode major depressive patients, who were above 18 years old and admitted in both psychiatric hospitals and units of general hospitals were recruited for the present study. These patients were newly treated and responded to 8-12 weeks of antidepressant treatment. Depressive symptoms, psychosocial functioning and quality of life were measured using standardized instruments. The study population was divided into three age groups: early adult (18-44 years old), middle adult (45-59 years old), and late adult (60-85 years old).Earlier age was associated with greater symptom severity, severer depressive symptoms in hypersomnia, concentration/decision making, negative view of the self, suicide ideation and restlessness, more impaired function, poorer satisfaction in social relationship and economic status, when compared to late adults with MDD (all P 0.05). In the multivariable analyses, among the other variables, early age remained as an independent correlation of residual depressive severity (middle age vs. early age: OR = 0.631, 95%CI[0.462, 0.862]; old age vs. early age: OR = 0.521, 95%CI[0.348, 0.780]) and functional impairment. Comorbidity of physical illness had a negative contribution to all treatment outcomes.In first major depressive episode, early age was strongly associated with depressive severity and functional impairment after responding to antidepressant treatment. Early-life depression may be an indicator of MDD for poor clinical outcomes and high clinical burden.

Aim Post-stroke depression (PSD) is one of the most frequent neuropsychiatric disorders associated with stroke characterized by depression. The neuroplasticity hypothesis postulates that loss of brain-derived neurotrophic factor (BDNF) plays a major role in pathophysiology of PSD, and restoration of it may represent a critical mechanism underlying antidepressant efficacy. Methods In previous studies, we designed a new fusion gene, HA2TAT-BDNF, and cloned it into adenovirus associated virus (AAV) to construct the BDNF-HA2TAT/AAV for the delivery of BDNF to central nervous system (CNS) via nose-brain pathway. In this study, we used it to explore the antidepressant effects on PSD rats through behavioral and various histological methods, and try to find out its specific mechanism. Results Compared with the control group, the PSD+AAV group showed decreased sucrose consumption percentage in the sucrose preference test (SPT) (P < 0.001) and prolonged immobility in the forced swimming test (FST) (P=0.000). However, the nasal administration of BDNF-HA2TAT/AAV reversed results of these two behavioral tests (P>0.05, P >0.05), showing an adequate antidepressant effect. Compared with the control group, the concentrations of BDNF mRNA and protein in the hippocampus (P< 0.05, P < 0.01) and prefrontal cortex (P < 0.01, P < 0.01) of PSD rats both decreased. Increased BDNF mRNA and protein expression was observed in the prefrontal cortex (P > 0.05, P < 0.05), without notable change in the hippocampus (P < 0.05, P < 0.001) of PSD+BDNF rats. Conclusion These results suggest that BDNF reductions in the prefrontal cortex and hippocampus are associated with the development of post-stroke depression, and that increased levels of BDNF in the prefrontal cortex could be used as a therapeutic target to treat PSD. However, the exact mechanism of BDNF action remains unclear in this regard, hindering the wider application of our method. We expect that our research could facilitate the exploration of pathogenesis and the new treatment method of PSD.

Objective: There is a lack of data about residual symptoms in Chinese patients with depression. The aim of this study was to evaluate the association of residual symptoms with social functional impairment in these patients. Methods: This was a multicenter cross-sectional study conducted in 11 hospitals in eight cities of China from September 2014 to April 2015. Residual symptoms and social functioning were assessed using the SDS, QIDS-SR16, Q-LES-Q-SF, and PHQ-15 scales. Logistic regression analysis was used to determine the factors associated with social functional impairment. Results: Among the 1503 patients, 915 (60.9%) had no functional impairment (SDS ≤6) and 588 (39.1%) showed functional impairment (SDS >6). Those with impairment had higher PHQ-15 scores (7.4 ± 4.8 vs. 4.0 ± 3.4, P

The default mode network (DMN) and its interaction with other key networks such as the salience network and executive network are keys to understand psychiatric and neurological disorders including major depressive disorder (MDD). In this study, we combined independent component analysis and seed based connectivity analysis to study the posterior default mode network between 20 patients with MDD and 25 normal controls, as well as pre-treatment and post-treatment conditions of the patients. Both correlated and anti-correlated networks centered at the posterior cingulate cortex (PCC) were examined (PCC+ and PCC-). Our results showed aberrant functional connectivity of the PCC+ and PCC- networks between patients and normal controls. Specifically, normal controls exhibited significantly higher connectivity between the PCC and frontal/temporal regions for the PCC+ network and stronger connectivity strength between the PCC and the insula/middle frontal cortex for the PCC- network. The overall connectivity strength of the PCC+ and PCC- networks was also significantly lower in MDD. Because the PCC is a hub in the DMN that interacts with other networks, our result suggested a stronger interaction between the DMN and the salience network but a weak interaction between the DMN and the executive network in MDD. The treatment using sertraline did increase the functional connectivity strength, especially in the PCC+ network. Despite a large inter-subject variability in the overall connectivity strengths and change of the PCC network in response to the treatment, a high correlation between change of connectivity strength and the Hamilton depression score was observed for both the PCC+ and PCC- network.

Cognitive impairment has been observed in patients with major depressive disorder (MDD). However, it remains unclear whether the deficits in specific cognitive domains are present in first-episode, drug-naïve patients or medicated patients. In the present study, using the CogState battery (CSB) Chinese language version, we evaluated the visual, working, and verbal memory in first-episode drug-naive patients and medicated patients with MDD in a Chinese population. We measured the cognitive function in first-episode drug-naïve patients (n = 36), medicated MDD patients (n = 71), and age- and sex-matched healthy control subjects (n = 59) in a Chinese population. The CSB composite scores in both first-episode drug-naive patients and medicated patients were significantly poorer than those in the healthy control subjects. The CSB sub-scores, including visual, working, and verbal memory were also significantly poorer in both patient groups than those in the healthy control subjects. In contrast, processing speed, attention/vigilance, executive function, spatial working memory, and social cognition were no different from healthy controls, whereas the executive function was significantly better in the medicated patients than in the healthy control subjects and first-episode drug-naïve patients. These findings suggest an impairment in the visual, working, and verbal memory in first-episode, drug-naive MDD patients in a Chinese population.

Social isolation (SI) rearing has been demonstrated to induce behavioral abnormalities like anxiety, impulsivity, aggression, and learning and memory deficits which are relevant to core symptoms in patients with some certain neuropsychiatric disorders. But the underlying pathophysiological mechanisms remain unclear. Recent studies have revealed HINT1 has close relation with diverse neuropsychiatric diseases. In this present study, the SI rearing mice exhibited depression-like and aggressive behavior. Besides, HINT1 protein levels decreased in PFC but increased in HIP. Based on the data obtained, we concluded that HINT1 is involved in the behavioral abnormalities induced by social isolation and exerts distinct roles in different encephalic regions.

Major depressive disorder (MDD), one of the most frequently encountered forms of mental illness and a leading cause of disability worldwide, poses a major challenge to genetic analysis. To date, no robustly replicated genetic loci have been identified, despite analysis of more than 9,000 cases. Here, using low-coverage whole-genome sequencing of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, we identified, and subsequently replicated in an independent sample, two loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene (P = 2.53 × 10(-10)), the other in an intron of the LHPP gene (P = 6.45 × 10(-12)). Analysis of 4,509 cases with a severe subtype of MDD, melancholia, yielded an increased genetic signal at the SIRT1 locus. We attribute our success to the recruitment of relatively homogeneous cases with severe illness.

Previous studies have found that the vaccinia related kinase 2 gene (VRK2) polymorphism was associated with schizophrenia (SCZ) in the worldwide population. This association was further supported by VRK2 mRNA expression patterns and brain structure variations. Here, we analyzed four single nucleotide polymorphisms (SNPs) of the VRK2 gene in a total population of 893 samples, consisting of 360 patients with SCZ and 533 healthy controls of Han Chinese descent using the SNPscan method. Single SNP, haplotype, and gender-specific association analyses were performed. We found that rs3732136 was significantly associated with SCZ (P = 0.042; odds ratio = 1.25; 95% confidence interval = 1.01-1.55). Further genotype and haplotype association analyses suggested a similar pattern. Our data provide preliminary evidence that the VRK2 gene might play a major role in the development of SCZ in the Northwest Chinese Han population.

Background Depression is associated with substantial personal suffering and reduced quality of life and functioning. The aim of this study was to investigate gender differences on quality of life and functional impairment of outpatients with depression after acute phase treatment. Methods 1503 depression outpatients were recruited from eleven hospitals in China. Subjects were evaluated with sociodemographic characteristics, history and self-report instruments, related to severity of symptoms, function and quality of life. All data were analyzed to determine the gender differences. Results Men had a younger age at onset and the first onset age, higher education compared to women in total patients and with or without residual symptoms group. Using regression analysis, it was found that gender was significantly statistically related to severity scores of SDS and had no correlation with Q-LES-Q-SF total scores. In the residual symptoms group, greater functional impairment was noted by men in the area of work and social life. Significant gender differences of mood, work and sexual life in quality of life were observed. Limitations This is a cross-sectional study of depressed outpatients and duration of acute phase treatment may not an adequate time to measure changes. Conclusions Depression appears to affect men more seriously than women after acute phase treatment. Men had a younger age at onset and the first onset age, higher education, more functional impairment and lower satisfaction of quality of life in mood, work and sexual life. Gender differences affect acute treatment, remission and recovery.

Previous findings on the dysfunction of hypothalamic-pituitary-adrenal (HPA) axis in generalized anxiety disorder (GAD) are controversial, and the molecular mechanisms underlying such dysfunction remain unclear. We analyzed the methylation status of the NR3C1 1

This study explores more polymorphisms in Disrupted-in-schizophrenia-1 (DISC1) for schizophrenia, which confer risk of developing the disorder.We report three short tandem repeat (STR) loci ((ATCC)n1, D1S1621, and (ATCC)n2) in DISC1 that showed a significant association with schizophrenia in a set of Chinese Han individuals, including 310 schizophrenics and 400 controls. The STRs in DISC1 associated with schizophrenia occur in intronic sequences in the vicinity of a critical splice junction that gives rise to the expression of DISC1 isoforms. The frequencies of allele 12 of (ATCC)n1, alleles 11 and 12, allele 13 and allele 15 of D1S1621, and allele 10 of (ATCC)n2 were significantly higher in schizophrenia patients than in controls. In contrast, the frequencies of alleles 9 and 10 of (ATCC)n1 and allele 16 and alleles17 and 18 of D1S1621 were significantly lower in schizophrenia patients than in controls.Our results provide further evidence for an effect of the DISC1 gene on the etiology of schizophrenia and suggest that STRs in the DISC1 gene may be genetic risk factors for schizophrenia.

Objective To determine the prevalence, associated factors and treatment status of alcohol use disorders (AUDs) in psychiatric patients in China. Methods We asked 24,379 consecutive patients aged ≥18years who presented at the psychiatric departments in eight hospitals in 2013 whether they had consumed alcoholic beverages in the previous month. Of the 2964 (12.2%) patients who answered yes and were then screened with the Alcohol Use Disorders Identification Test (AUDIT), 1304 (5.3%) screened positive (AUDIT≥7) and, based on DSM-IV criteria, were diagnosed with AUDs by psychiatrists. The treatments prescribed for them were also recorded. Logistic regression was used to identify AUDs associated factors. Results The prevalence of AUDs was 2.4% (95% CI: 2.2–2.6%). None of the patients diagnosed with AUDs had got medical treatment for preventing relapse. The risk factors for AUDs were middle-aged or elderly (OR=1.86, 95% CI: 1.23–2.80), and consuming beverages with high degree of alcohol content (OR=2.92, 95% CI: 2.11–4.06). Conclusions The prevalence of AUDs in psychiatric patients in China was not high, but the rate of treatment was dramatically low, indicating the serious neglect of AUDs. Our study suggests an urgent need to improve the situation of unmet need for treatment of psychiatric patients with AUDs.

Depression is a disturbing psychiatric disease with unsatisfied therapy. Not all patients are sensitive to anti-depressants currently in use, side-effects are unavoidable during therapy and the cases with effectiveness are always accompanied with delayed onset of clinical efficacy. Delivering brain-derived neurotrophic factor (BDNF) to brain seems to be a promising therapy. However, a better approach to delivery is still rudimentary. The purpose of our present work is to look for a rapid-onset and long-lasting therapeutic strategy for major depressive disorder (MDD) by effectively delivering BDNF to brain. BDNF, fused with cell-penetrating peptides (TAT and HA2), was packaged in adenovirus associated virus (AAV) to construct the BDNF-HA2TAT/AAV for intranasally delivering BDNF to central nervous system (CNS) via nose-brain pathway. Intranasal administration of BDNF-HA2TAT/AAV to normal mice displayed anti-depression effect in forced swimming test when the delivery lasted relatively longer. The AAV applied to mice subjected to chronic mild stress (CMS) through intranasal administration for 10 days also alleviated depression-like behaviors. Western-blotting analysis revealed that BDNF-HA2TAT/AAV nasal administration enhanced hippocampal BDNF content. These results indicate intranasal administration of constructed BDNF-HA2TAT/AAV exerts anti-depression effect in CMS mice by increasing hippocampal BDNF, suggesting that this strategy holds a promising therapeutic potential for MDD.

Recently, a new schizophrenia susceptibility locus 10q24.32–q24.33, containing two single-nucleotide polymorphisms (SNPs: rs7914558 and rs11191580), was identified in a genome-wide association study. To examine if this locus is associated with schizophrenia in the Han Chinese population, we analyzed six SNPs, including two SNPs within the region of interest. The sample consisted of 1430 schizophrenia cases and 1570 controls from genetically independent members of the Han population. Single-SNP association, haplotype association and sex-specific association analyses were performed. Three SNPs, rs7914558 (p = 1.41 × 10− 4; OR = 1.11; 95% CI 1.05–1.17), rs12220375 (p = 1.18 × 10− 4; OR = 1.06; 95% CI 1.03–1.09) and rs11191580 (p = 3.03 × 10− 4; OR = 1.05; 95% CI 1.02–1.10), mapped to the locus and were significantly associated in our sample set. Further genotype and haplotype association analyses suggested a similar pattern. Similar to results from European populations, our results provide further evidence that this region associated with schizophrenia in Han Chinese. Results also confirm previous reports suggesting that 10q24.32–q24.33 offers an intriguing new insight into the pathogenesis of schizophrenia and may play an important role in its etiology.

BACKGROUND: Post partum depression (PPD) is relatively common in China but its clinical characteristics and risk factors have not been studied. We set out to investigate whether known risk factors for PPD could be found in Chinese women. METHODS: A case control design was used to determine the impact of known risk factors for PPD in a cohort of 1970 Chinese women with recurrent DSM-IV major depressive disorder (MDD). In a within-case design we examined the risk factors for PPD in patients with recurrent MDD. We compared the clinical features of MDD in cases with PPD to those without MDD. Odds ratios were calculated using logistic and ordinal regression. RESULTS: Lower occupational and educational statuses increased the risk of PPD, as did a history of pre-menstrual symptoms, stressful life events and elevated levels of the personality trait of neuroticism. Patients with PPD and MDD were more likely to experience a comorbid anxiety disorder, had a younger age of onset of MDD, have higher levels of neuroticism and dysthymia. LIMITATIONS: Results obtained in this clinical sample may not be applicable to PPD within the community. Data were obtained retrospectively and we do not know whether the correlations we observe have the same causes as those operating in other populations. CONCLUSIONS: Our results are consistent with the hypothesis that the despite cultural differences between Chinese and Western women, the phenomenology and risk factors for PPD are very similar.

BACKGROUND: In European and US studies, patients with major depressive disorder (MDD) report more stressful life events (SLEs) than controls, but this relationship has rarely been studied in Chinese populations. METHODS: Sixteen lifetime SLEs were assessed at interview in two groups of Han Chinese women: 1970 clinically ascertained with recurrent MDD and 2597 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression. RESULTS: 60% of controls and 72% of cases reported at least one lifetime SLE. Fourteen of the sixteen SLEs occurred significantly more frequently in those with MDD (median odds ratio of 1.6). The three SLEs most strongly associated with risk for MDD (OR>3.0) preceded the onset of MDD the majority of the time: rape (82%), physical abuse (100%) and serious neglect (99%). LIMITATIONS: Our results may apply to females only. SLEs were rated retrospectively and are subject to biases in recollection. We did not assess contextual information for each life event. CONCLUSIONS: More severe SLEs are more strongly associated with MDD. These results support the involvement of psychosocial adversity in the etiology of MDD in China.

BACKGROUND: Individuals with early-onset depression may be a clinically distinct group with particular symptom patterns, illness course, comorbidity and family history. This question has not been previously investigated in a Han Chinese population. METHODS: We examined the clinical features of 1970 Han Chinese women with DSM-IV major depressive disorder (MDD) between 30 and 60 years of age across China. Analysis of linear, logistic and multiple logistic regression models was used to determine the association between age at onset (AAO) with continuous, binary and discrete characteristic clinical features of MDD. RESULTS: Earlier AAO was associated with more suicidal ideation and attempts and higher neuroticism, but fewer sleep, appetite and weight changes. Patients with an earlier AAO were more likely to suffer a chronic course (longer illness duration, more MDD episodes and longer index episode), increased rates of MDD in their parents and a lower likelihood of marriage. They tend to have higher comorbidity with anxiety disorders (general anxiety disorder, social phobia and agoraphobia) and dysthymia. CONCLUSIONS: Early AAO in MDD may be an index of a more severe, highly comorbid and familial disorder. Our findings indicate that the features of MDD in China are similar to those reported elsewhere in the world.

Recent developments in depression studies have heightened the need for investigating adolescent major depressive disorder (MDD). Many previous neuroimaging studies used task designs and found consistent results in the dysfunction of brain regions in depressed adolescent patients. In this study, we aimed to evaluate the topological properties of brain functional networks of adolescents with MDD from an integrated view. Using resting state functional magnetic resonance imaging (fMRI), graph theory was applied to construct the resting networks in 16 first-episode and unmedicated adolescents with MDD and 16 healthy controls (HC). Our results showed that the topological properties of depressed adolescents' networks were significantly disrupted compared with HC. Dysregulation of brain regions were found in the anterior cingulate cortex, dorsolateral, medial and inferior prefrontal cortex, insula, amygdala, and the temporal cortices. Furthermore, the connectivity degree of amygdala related functional connection was positively correlated with the duration of depression. Detection and estimation of these functional impairments may advance our current understanding of the pathophysiological mechanism of adolescent MDD.

Objective The personality trait of neuroticism is a risk factor for major depressive disorder (MDD), but this relationship has not been demonstrated in clinical samples from Asia. Methods We examined a large-scale clinical study of Chinese Han women with recurrent major depression and community-acquired controls. Results Elevated levels of neuroticism increased the risk for lifetime MDD (with an odds ratio of 1.37 per SD), contributed to the comorbidity of MDD with anxiety disorders, and predicted the onset and severity of MDD. Our findings largely replicate those obtained in clinical populations in Europe and US but differ in two ways: we did not find a relationship between melancholia and neuroticism; we found lower mean scores for neuroticism (3.6 in our community control sample). Limitations Our findings do not apply to MDD in community-acquired samples and may be limited to Han Chinese women. It is not possible to determine whether the association between neuroticism and MDD reflects a causal relationship. Conclusions Neuroticism acts as a risk factor for MDD in Chinese women, as it does in the West and may particularly predispose to comorbidity with anxiety disorders. Cultural factors may have an important effect on its measurement.

Chinese herbal medicines possess the therapeutic potential for mood disorders. This double-blind, randomized, placebo-controlled study was designed to evaluate the efficacy and side effects of the herbal medicine called Free and Easy Wanderer Plus (FEWP) as an adjunct to carbamazepine (CBZ) in patients with bipolar disorders. One hundred and twenty-four bipolar depressed and 111 manic patients were randomized to treatment with CBZ alone, CBZ plus FEWP, or equivalent placebo for 12 weeks. CBZ was initiated at 300mg/day and FEWP was given at a fixed dose of 36g/day. Efficacy measures included the Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale , Young Mania Rating Scale, Bech-Rafaelsen Mania Scale, and Clinical Global Impression-Severity (CGI-S). CBZ monotherapy produced significantly greater improvement on manic measures at week 2 through endpoint and CGI-S of depression at endpoint compared to placebo. CBZ monotherapy also yielded significantly higher clinical response rates than placebo on bipolar depression (63.8% vs. 34.8%, p=0.044) and mania (87.8% vs. 57.1%, p=0.012). Compared to CBZ monotherapy, adjunctive FEWP with CBZ resulted in significantly better outcomes on the three measures of depression at week 4 and week 8 and significantly greater clinical response rate in depressed subjects (84.8% vs. 63.8%, p=0.032), but failed to produce significantly greater improvement on manic measures and the response rate in manic subjects. There was a lesser incidence of dizziness and fatigue in the combination therapy compared to CBZ monotherapy. These results suggest that adjunctive FEWP has additive beneficial effects in bipolar patients, particularly for those in depressive phase.

The present study was designed to construct a recombinant adeno-associated virus (rAAV) which can express NAP in the brain and examine whether this virus can produce antidepressant effects on C57 BL/6 mice that had been subjected to open field test and forced swimming test, via nose-to-brain pathway. When the recombinant plasmid pGEM-T Easy/NT4-NAP was digested by EcoRI, 297 bp fragments can be obtained and NT4-NAP sequence was consistent with the designed sequence confirmed by DNA sequencing. When the recombinant plasmid pSSCMV/NT4-NAP was digested by EcoRI, 297 bp fragments is visible. Immunohistochemical staining of fibroblasts revealed that expression of NAP was detected in NT4-NAP/AAV group. Intranasal delivery of NT4-NAP/AAV significantly reduced immobility time when the FST was performed after 1 day from the last administration. The effects observed in the FST could not be attributed to non-specific increases in activity since intranasal delivery of NT4-NAP/AAV did not alter the behavior of the mice during the open field test. The results indicated that a recombinant AAV vector which could express NAP in cells was successfully constructed and NAP may be a potential target for therapeutic action of antidepressant treatment.

Background We sought to investigate the clinical features of and risk factors for recurrent major depression (MD) with history of postpartum episodes (PPD) in Han Chinese women and the differences between first-onset postpartum MD (MD that has its first lifetime depressive episode in the postpartum period) and first-onset non-postpartum MD (MD with history of PPD and has its first lifetime depressive episode in a period other than postpartum). Methods Data were derived from the China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE) study (N=6017 cases) and analyzed in two steps. We first examined the clinical features of and risk factors for MD patients with (N=981) or without (N=4410) a history of PPD. We then compared the differences between first-onset postpartum MD (N=583) and first-onset non-postpartum MD (N=398) in those with a history of PPD. Linear, logistic and multinomial logistic models were employed to measure the associations. Results A history of PPD was associated with more guilt feelings, greater psychiatric comorbidity, higher neuroticism, earlier onset and more chronicity (OR 0.2–2.8). Severe premenstrual symptoms (PMS) and more childbirths increased the risk of PPD, as did a family history of MD, childhood sexual abuse, stressful life events and lack of social support (OR 1.1–1.3). In the MD with history of PPD subsample, first-onset postpartum MD was associated with fewer recurrent major depressive episodes, less psychiatric comorbidity, lower neuroticism, less severe PMS and fewer disagreements with their husbands (OR 0.5–0.8), but more childbirths (OR 1.2). Limitations Data were obtained retrospectively through interview and recall bias may have affected the results. Conclusions MD with history of PPD in Han Chinese women is typically chronic and severe, with particular risk factors including severe PMS and more childbirths. First-onset postpartum MD and first-onset non-postpartum MD can be partly differentiated by their clinical features and risk factors, but are not clearly distinctive.

To explore how coping style and social support influence the quality of life in patients with impaired glucose tolerance, which act respectively as the internal and external mediating ways.A total of 283 patients with impaired glucose tolerance from 6 Three-A hospitals in China were surveyed with self-rating anxiety scale, self-rating depression scale, trait coping style questionnaire, social support scale, and WHOQOL-BREF.Biographic data failed to predict the quality of life in patients with impaired glucose tolerance, while anxiety, depression, social support and coping style significantly influenced their quality of life.The fact that emotional disorder, social support and coping style influence the quality of life in patients with type 2 diabetes also exists in patients with impaired glucose tolerance.

Major depressive disorder (MDD) is a common, recurrent mental illness that affects millions of people worldwide. Accumulating evidence suggests that the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, plays an important role in the neurobiology and treatment of this disease. Currently, the non-competitive NMDA receptor antagonist ketamine is considered as one of the most attractive candidate drugs in therapy of treatment-resistant depression. A recent study demonstrated ketamine's rapid antidepressant activity in patients with treatment-resistant MDD and bipolar disorder. The response rate for ketamine ranged from 25% to 85% at 24 hours post-infusion and from 14% to 70% at 72 hours post-infusion, with generally mild adverse effects. Based on the role of the NMDA receptor in depression, a number of therapeutic drugs which interact with this receptor have been developed. In this article, we reviewed recent findings concerning the role of glutamatergic signaling in the neurobiology of MDD and potential, novel therapeutic drugs, such as ketamine, memantine, AZD6765, traxoprodil, MK-0657, GLYX-13, NRX-1047, D-cycloserine, sarcosine, all of which target this system.